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Chromosomal Genetic Disorders — Robbins Pathology

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1. Background & Classification

1. Monogenic (Mendelian) disorders — single gene mutations with large effect, follow classic inheritance
2. Chromosomal disorders — abnormal number or structure of chromosomes (this chapter)
3. Complex multigenic disorders — multiple genes + environment (diabetes, hypertension)

• Loss of chromosomal material → more severe defects than gain
• Autosomal monosomy → generally lethal (too much gene loss); autosomal trisomy → less severe but still major
• Sex chromosome imbalances are tolerated much better than autosomal ones — explained by lyonization and the Y chromosome carrying little genetic information
• Sex chromosome disorders are often subtle, not detected at birth; infertility is the commonest presentation
• Most chromosomal disorders arise de novo (parents are normal; recurrence risk in siblings is low) — except translocation Down syndrome

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2. The Normal Karyotype & Cytogenetic Basics

2.1 How Karyotyping is Done

• Dividing cells arrested in metaphase using mitotic spindle inhibitors (e.g., colchicine)
• Stained with Giemsa (G-banding) → alternating light and dark bands
• Standard G-banding resolves ~400–800 bands per haploid set; prophase banding → up to 1500 bands
• Normal: 46,XX (female), 46,XY (male)

2.2 Cytogenetic Notation

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3. Types of Chromosomal Abnormalities

3.1 Numerical Abnormalities

• Nondisjunction — failure of chromosomes to separate during meiosis I or II (or mitosis) → gametes with n+1 or n−1 chromosomes
• Anaphase lag — a chromosome lags behind and is excluded from the nucleus → one normal cell + one monosomic cell

3.2 Structural Abnormalities

Pearl: Balanced structural rearrangements → phenotypically normal carriers, but produce aneuploid gametes at meiosis (risk of affected offspring). Unbalanced rearrangements → phenotypic abnormalities.

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4. Cytogenetic Disorders Involving Autosomes

4.1 Trisomy 21 — Down Syndrome ⭐ (Most Important)

• < 20 years: 1 in 1550 live births

• 45 years: 1 in 25 live births

• In 95% of cases, the extra chr 21 is of maternal origin

• Cell-free fetal DNA (cfDNA) from maternal blood → next-generation sequencing → highly sensitive noninvasive screen
• Confirmed by conventional karyotyping of chorionic villus sample or amniotic fluid

• APP → Alzheimer disease
• SOD1 → excess free radicals (mitochondrial dysfunction)
• Highest density of lncRNAs of any chromosome (functions largely unknown)

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4.2 Trisomy 18 — Edwards Syndrome

• Rocker-bottom feet, overlapping fingers (index finger over 3rd, 5th over 4th)
• Micrognathia, prominent occiput
• Severe congenital heart defects
• Intellectual disability, hypertonia
• Renal malformations

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4.3 Trisomy 13 — Patau Syndrome

• Holoprosencephaly (failure of forebrain division)
• Cleft lip/palate
• Microphthalmia/anophthalmia, cyclopia
• Polydactyly
• Congenital heart defects (VSD, ASD, PDA)
• Cutis aplasia (absent skin patches on scalp — pathognomonic)

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4.4 Chromosome 22q11.2 Deletion Syndrome (DiGeorge / Velocardiofacial)

• Schizophrenia in ~25% of adults (2–3% of childhood-onset schizophrenia have this deletion)
• ADHD in 30–35% of affected children
• Atopic disorders, autoimmunity

Pearl: 30% of individuals with conotruncal cardiac defects alone also harbor 22q11.2 deletions.

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5. Cytogenetic Disorders Involving Sex Chromosomes

Why sex chromosome disorders are better tolerated — Lyon Hypothesis

• Occurs early in fetal life (~16 days post-conception)
• Random — either maternal or paternal X is silenced in each cell
• All progeny of that cell maintain the same inactive X (clonal)
• Molecular basis: XIST gene → encodes a long noncoding RNA that "coats" the X chromosome from which it is transcribed → silences genes on that X; the other XIST allele is switched off in the active X

• Not all genes on the inactive X are silent: ~30% of genes on Xp and ~3% on Xq escape X inactivation — this explains phenotypic effects in Turner syndrome (monosomy X)
• All X chromosomes beyond one are inactivated, so even 48,XXXX females have only one active X
• Y chromosome carries little genetic information — the critical gene is SRY (sex-determining region Y) on Yp → dictates male phenotype regardless of number of X chromosomes present

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5.1 Klinefelter Syndrome ⭐

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5.2 Turner Syndrome ⭐

Pearl: Mosaics with a high proportion of 46,XX cells may have nearly normal appearance and present only with primary amenorrhea. A very small number can conceive.

Pearl: 5–10% of Turner patients have Y chromosome sequences (45,X/46,XY or Y fragments) → significantly higher risk of gonadoblastoma → prophylactic gonadectomy indicated.

• Lymphedema of dorsum of hands and feet
• Cystic hygroma (distended lymphatics at nape of neck) → may be detected on prenatal US
• Webbed neck (pterygium colli) — residual from resolved hygroma

• Coarctation of aorta (preductal) — ~5% of females with coarctation have Turner syndrome
• Bicuspid aortic valve (most common cardiac anomaly overall)
• Aortic root dilation (30%); aortic dissection risk ×100 vs. normal

• Short stature (rarely >150 cm) — most consistent feature
• Primary amenorrhea and failure to develop secondary sex characteristics
• Streak gonads (bilateral fibrous streaks replacing ovaries) → infertility
• Infantile genitalia, poor breast development, scant pubic hair
• Shield chest, widely spaced nipples
• Low posterior hairline, high arched palate
• Cubitus valgus (wide carrying angle)
• Normal intellect but subtle deficits in nonverbal/visual-spatial processing
• ~50% develop autoimmune thyroiditis (hypothyroidism)
• Glucose intolerance, obesity

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5.3 Other Sex Chromosome Aneuploidies (Brief)

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6. Hermaphroditism and Pseudohermaphroditism (Brief Overview)

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7. Summary Comparison Table — High-Yield for Exams

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8. Diagnostic Methods — Cytogenetic & Molecular

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9. Key Exam Pearls (Robbins)

1. Nondisjunction is the most common cause of aneuploidy; anaphase lag produces monosomy only
2. Monosomy of an autosome is almost always lethal; trisomies 21, 18, 13 survive
3. Maternal age matters for free trisomies (nondisjunction); it does NOT matter for translocation or mosaic Down syndrome
4. Robertsonian translocation: carrier has 45 chromosomes but normal phenotype; risk of Down syndrome offspring is high
5. Turner syndrome = most common cause of primary amenorrhea; 45,X is the most frequent karyotype
6. Klinefelter = most common cause of male hypogonadism/infertility due to chromosomal cause
7. Lyon hypothesis: X-inactivation starts day 16; mediated by XIST lncRNA; ~30% of Xp genes escape inactivation
8. 22q11.2 deletion: diagnose with FISH; TBX1 is the key gene; psychiatric risk = 25% schizophrenia
9. All Down syndrome patients >40 years → Alzheimer disease (APP gene on chr 21)
10. Y-material in Turner syndrome → gonadoblastoma risk → gonadectomy

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